Human periodontal diseases are inflammatory disorders that are the result of complex interactions between periodontopathogens and the host's immune response. It is believed that there are two interrelated aspects to the progression of periodontal disease, the first is the activation of the immune system of the host and the second is the production of oxygen radicals and their related metabolites. Increased production of oxygen radicals may contribute to oxidative stress, which is believed to be involved in periodontal disease.
Gingivitis is the inflammation or infection of the gums and the alveolar bones that support the teeth. Gingivitis is generally believed to be caused by bacteria in the mouth (particularly the bacteria instigated in plaque formation) and the toxins formed as by-products from the bacteria. The plaque and bacterial toxins are believed to instigate oral tissue inflammation within the mouth. Periodontitis is a progressively worsened state of disease as compared to gingivitis, where the gums are inflamed and begin to recede from the teeth and pockets form in the recession, which ultimately may result in destruction of the bone and periodontal ligament. Thus, chronic infection and inflammation potentially results in the subsequent loss of teeth. Further, oral tissue inflammation can be caused by surgery, localized injury, trauma, or necrosis, or various systemic origins.
It is generally believed that the cellular components implicated by these diseases and conditions include epithelial tissue, gingival fibroblasts, and circulating leukocytes, all of which contribute to the host response to pathogenic factors generated by the bacteria. Thus, bacterial infection of the oral tissue ramps up the host's immune response and diminishes the healing process by generating free radical species (reactive oxygen species) and up-regulating inflammatory mediators that cause significant tissue damage.
Free radicals are atoms, ions, or molecules that contain an unpaired electron, and as such are usually unstable and exhibit short half-lives. Reactive oxygen species (ROS) are products produced during various biochemical processes, and include superoxide anions (O2−), hydrogen peroxide (H2O2), hydroxyl radicals (OH−), and non-radical oxidants such as singlet oxygen (1O2). The formation of ROS can occur as part of many cellular processes including mitochondrial respiration, immune cell responses, cell injury, heat, radiation of many origins, from metabolism of drugs and other chemicals. The ROS are highly reactive and modify important cellular macromolecules. ROS initiate or accelerate disease processes.
In one example, ROS are generated during inflammation by phagocytic leukocytes, such as activated neutrophils that produce an “oxidative burst” of superoxide radicals, which are believed to be an essential factor in producing the cytotoxic effect of activated neutrophils. Moreover, superoxide may be produced physiologically by endothelial cells for reaction with nitric oxide, a physiological regulator, forming peroxynitrite, ONOO− which may decay and give rise to hydroxyl radical, OH. Additional sources of oxyradicals are “leakage” of electrons from disrupted mitochondrial or endoplasmic reticular electron transport chains, prostaglandin synthesis, oxidation of catecholamines, and platelet activation.
ROS are thought to be involved in almost all disease processes and the ageing process. Increased ROS formation under pathological conditions is believed to cause cellular damage through the action of these highly reactive molecules by crosslinking proteins, mutagenizing DNA, and peroxidizing lipids.
Another aspect of the immune response is the production of various intra and inter-cellular mediators of inflammation. One class of mediators extensively studied for their effect on the inflammatory response are the arachidonic acid metabolites namely prostaglandins and leukotrienes, that are produced through the cyclooxygenase or lipoxygenase enzyme pathways. These metabolites have been implicated as the prime mediators in gingivitis, periodontitis, osteomyelitis and other inflammatory diseases.
It would be desirable to have a method of treating a mammalian subject having infection, inflammation, and potential cellular damage in oral tissue, by killing the etiological pathogens of infection, reducing the production of one or more mediators of inflammation, and reducing free radical reactive oxygen species to reduce cellular damage to the oral tissue to promote healing.